The Institute of Medicine, Qiqihar Medical University, Qiqihar, China.
Department of Hematology, the First Affiliated Hospital, Harbin Medical University, Harbin, China.
J Nutr Biochem. 2021 May;91:108603. doi: 10.1016/j.jnutbio.2021.108603. Epub 2021 Feb 4.
Prenatal and/or early postnatal exposure to lead (Pb) may be associated with deficits in cognitive function in the toddler offspring, and oxidative stress likely play a central role in mediating these adverse effects. Here, we tested the hypothesis that ameliorative effect of ferulic acid (FA) on lead-induced cognitive deficits attributed to its antioxidant properties in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent manner in the context of prenatal Pb exposure. To test this hypothesis, Nrf2 knockout and C57BL/6 wild type mouse dams were exposed/unexposed to PbAc (250 ppm) during gestation day 5 to postnatal day 14 via drinking water, and FA (50 mg/kg)/vehicle was administered orally to dams for 31 d. Spatial learning and memory in pups was assessed by Morris water maze. Biochemical assays, real-time PCR, western blot techniques were employed to evaluate oxidative stress and signaling pathways in the brain of pups. We report that lead acetate (PbAc) leads to deficits in cognitive functions in offspring, which were partially attenuated by FA (P<.05). In parallel, pretreatment with FA also significantly inhibited the PbAc-induced oxidative stress, as indicated by a change in NAD+/NADH ratio, glutathione (GSH) and malondialdehyde contents (all P<.05). Interestingly, FA significantly elevated the glutamate cysteine ligase and heme oxygenase 1 at levels of transcription and translation in both mice exposed and unexposed to Pb, increasing de novo synthesis of GSH (all P<.05). Furthermore, maternal FA administration activates extracellular signal-regulated kinases 1 and 2 and promotes more Nrf2 nuclear accumulation by increasing the Nrf2 total protein in brain of offspring mice (all P<.05). Conversely, FA failed to influence Pb-induced both memory deficits and oxidative stress in offspring of Nrf2 knockout mice (all P≥.05), suggesting that Nrf2 is essential in mediating the cognition-enhancing and antioxidant effects of FA. Overall, our results demonstrate that FA protects against Pb-induced offspring's cognitive deficits, suggesting that it is a promising candidate for the treatment of Pb toxicity.
产前和/或产后早期接触铅（Pb）可能与幼儿后代认知功能缺陷有关，氧化应激可能在介导这些不利影响中起核心作用。在这里，我们测试了这样一种假设，即在产前 Pb 暴露的情况下，阿魏酸（FA）通过核因子（红系衍生 2）样 2（Nrf2）依赖性方式发挥其抗氧化特性，从而改善 FA 对铅诱导的认知缺陷的作用。为了验证这一假设，Nrf2 敲除和 C57BL/6 野生型母鼠在妊娠第 5 天至第 14 天通过饮用水暴露/不暴露于 PbAc（250ppm），并在第 31 天经口给予 FA（50mg/kg）/载体。通过 Morris 水迷宫评估幼鼠的空间学习和记忆能力。生物化学测定、实时 PCR、western blot 技术用于评估幼鼠大脑中的氧化应激和信号通路。我们报告说，醋酸铅（PbAc）导致后代认知功能缺陷，FA 可部分减轻（P<.05）。平行地，FA 预处理也显著抑制了 PbAc 诱导的氧化应激，这表现在 NAD+/NADH 比、谷胱甘肽（GSH）和丙二醛含量的变化（均 P<.05）。有趣的是，FA 显著提高了谷氨酸半胱氨酸连接酶和血红素加氧酶 1 的转录和翻译水平，增加了 GSH 的从头合成（均 P<.05）。此外，母体 FA 给药通过增加幼鼠脑中 Nrf2 的总蛋白，激活细胞外信号调节激酶 1 和 2，并促进更多的 Nrf2 核积累，从而增强后代的 Nrf2 核积累（均 P<.05）。相反，FA 未能影响 Nrf2 敲除小鼠后代的记忆缺陷和氧化应激（均 P≥.05），表明 Nrf2 是介导 FA 增强认知和抗氧化作用的关键。总的来说，我们的结果表明 FA 可预防 Pb 诱导的后代认知缺陷，表明它是治疗 Pb 毒性的有前途的候选药物。
